Alzheimer disease (AD) which is a representative disease of senile dementia is a degenerative disease characterized by atrophy of brain, deposition of senile plaque and formation of neurofibril, and neuronal loss is considered to induce the dementia symptom (N. Eng. J. Med. 2003; 348:1356). In AD, an amyloid precursor protein (APP) which is a single transmembrane protein is cleaved at an extracellular part thereof by β-secretase in lipid rafts (cell membrane microdomain where sphingolipid and cholesterol are integrated) rather than by α-secretase in cell membrane, and further, the transmembrane part of the molecule is cleaved by γ-secretase to produce Aβ40 and Aβ42. Above all, deposition of the Aβ42 peptide which has highly cohesive property in the brain causes neuronal loss and leads to atrophy of the brain. In contrast to the β-secretase of single transmembrane protein, the γ-secretase is considered to be a complex composed by association of an active subunit of presenilin with nicastrin, APH-1 and Pen-2 (SEITAI NO KAGAKU 2003; 291-296), and to be involved in the production of Aβ40 and Aβ42 in lipid rafts. It has been reported that the cholesterol level may affect the secretase activity, for instance, increased level of cholesterol decreases the α-secretase activity but increases the β-secretase activity, while the γ-secretase activity is not largely affected (Biochem. Soc. Transact. 2002; 30: 525-529). With respect to the γ-secretase activity after removal of cholesterol from the lipid raft using a cholesterol inclusion compound (J. Lipid Res. 1999; 40: 781-796), there are two different findings; one paper reported disappearance of the γ-secretase activity (Neurobiol. Res. 2002; 30: 525-529); and the other paper reported no influence on the γ-secretase activity (Biochemistry 2003; 42: 13977-13986).
Biosynthetic process of cholesterol is initiated by a step of the formation of mevalonic acid from 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) by a HMG-CoA reductase, where the HMG-CoA is produced from acetyl-CoA by a HMG-CoA synthetase. The resultant mevalonic acid is converted to isopentenyl pyrophosphate referred to as an active isoprene unit, and then converted through geranyl pyrophosphate to farnesyl pyrophosphate by a farnesyl pyrophosphate synthetase. Subsequently, farnesyl pyrophosphate is converted to squalene by a squalene synthetase, then to 2,3-epoxysqualene by a squalene epoxidase. Thereafter, 2,3-epoxysqualene is converted to lanosterol by a lanosterol synthetase to form a basic structure of cholesterol, and finally cholesterol is produced through various modification reactions.
A part of farnesyl pyrophosphate formed by a farnesyl pyrophosphate synthetase reacts with isopentenyl pyrophosphate to form geranylgeranyl pyrophosphate, which is used for geranylgeranylation of proteins such as Rho and Rac by an action of a geranylgeranyl transferase.
Also, as AMPK inactivates the HMG-CoA reductase by phosphorylation, an AMPK activating agent may exert the similar effect as HMG-CoA reductase inhibitor. Further more, the AMPK also has an effect to phosphorylate and inactivate an acetyl-CoA carboxylase, so that synthesis of fatty acid is suppressed accordingly. Also, it has been known that fibrate also has an action to inhibit HMG-CoA reductase through activation of AMPK.
The inhibitor of HMG-CoA reductase is an agent to inhibit antagonistically the HMG-CoA reductase which catalyzes the conversion of HMG-CoA into mevalonic acid at a rate-limiting step of cholesterol biosynthesis, and has been known as a therapeutic agent for hypercholesteremia. A retrospective epidemiological study has demonstrated that a patient who takes the HMG-CoA reductase inhibitor shows a low AD prevalence rate (Arch. Neurol. 2000; 57: 1439-1433) and also that the HMG-CoA reductase inhibitor decreases the formation of Aβ peptide in vitro and in vivo. Based on the above findings, the usefulness of the HMG-CoA reductase inhibitor for the treatment of AD has been applied for patents (WO 02/062824, WO 01/096311, WO 01/32161, WO 00/28981, WO 99/48488, U.S. Pat. Nos. 6,472,421, 6,440,387, 6,080,778). In the specifications of these patents, it has been described a possibility of the HMG-CoA reductase inhibitor to decrease the production of Aβ peptide through processing of APP, namely through controlling secretase activity, however, there is no description about the decrease of γ-secretase activity.
There has currently been an active study on γ-secretase inhibitor as a therapeutic agent for AD (Adv. Drug Deliv. Rev. 2002; 54: 1579-1588) from the reasons such as the γ-secretase is an enzyme to produce Aβ42 peptide, and that genetic mutation of presenilin which is an active subunit of the enzyme can be the cause of AD (Arch. Neurol. 2003; 60: 1541-1544). However, the γ-secretase cleaves not only APP but also Notch, ErbB4, CD44, LRP and the like, and the enzyme with high potency may cause adverse reaction (FASEB J. 2003; 17: 79-81), therefore, development of γ-secretase inhibitor has not always progressed successfully. In the existing drugs, it has been reported that some nonsteroidal antiinflammatory drug having inhibitory activity for γ-secretase specifically blocked the production of Aβ42 without inhibiting the cleavage of Notch (J. Biol. Chem. 2003; 278:30748-30754, J. Biol. Chem. 2003; 278: 18664-18670). With respect to a mechanism of action of the drug, involvement of Rho suppression has been suggested (Science 2003; 302: 1215-1217).